The role of blood urea nitrogen to serum albumin ratio in the prediction of severity and 30‐day mortality in patients with COVID‐19

Abstract Background Considering the role of higher blood urea nitrogen and lower serum albumin (SA) levels in deceased coronavirus disease 2019 (COVID‐19) patients, an increased blood urea nitrogen to SA (B/A) ratio may help to determine those at higher risk of critical illness. This study aimed to evaluate the correlation of the B/A ratio with severity and 30‐day mortality in COVID‐19 patients. Methods A total of 433 adult patients with COVID‐19 were enrolled. The laboratory markers were measured on admission. Disease severity was categorized into mild disease, severe pneumonia, acute respiratory distress syndrome (ARDS), sepsis, and septic shock. The mortality was followed for 30 days after admission. χ 2 test, Fisher's exact test, and Mann–Whitney U test were performed, as appropriate. Also, logistic regression and the receiver operating characteristic (ROC) curve for the B/A ratio are included. Results Thirty‐day mortality rate was 27.25%. The frequency of mild, severe pneumonia, ARDS, sepsis, and septic shock was 30.72%, 36.95%, 24.02%, 6.00%, and 2.31%, respectively. B/A ratio and SA levels were statistically different between alive and deceased patients. The mean B/A ratio was different among classified disease severities, except for mild disease. Logistic regression revealed the B/A ratio as an independent risk factor for sepsis after adjusting for age and sex. ROC analysis showed B/A ratio had an area under the curve (AUC) of 0.733 for mortality at the cutpoint of 4.944. AUC for sepsis was 0.617 which was greater than other disease severities. Conclusion The results showed that B/A ratio and SA levels are associated with mortality of COVID‐19 patients. A higher B/A ratio is, additionally, associated with COVID‐19 severity, except in mild cases and it can act as an independent risk factor in sepsis. However, a greater B/A ratio is not a significant predictor of COVID‐19 severity, but it can predict mortality. Therefore, we suggest this marker for clinical assessment of patients with severe COVID‐19.


| INTRODUCTION
Coronavirus disease 2019 , also known as the 2019 novel coronavirus, is the most critical issue around the world today. 1 It has started in Wuhan, China, in December 2019 and spread around the world quickly by human-to-human transmission, and is announced as a pandemic respiratory disease by the World Health Organization (WHO) in March 2020. COVID-19 is infecting more patients each day with worldwide mortality exceeding 4 million to date (August 2021). [2][3][4][5] The main site of infection in COVID-19 is the respiratory system and the main clinical presentations include fever, cough, breathlessness, and pneumonia. Severe cases with acute respiratory distress syndrome (ARDS) require intensive care unit (ICU) admission and mechanical ventilation. Multiple organ failure may occur in some cases of COVID-19 and result in death. 1 In contrast, some may remain asymptomatic and act as carriers. 6 In addition, COVID-19 may have a long incubation period. 7 Accordingly, it is important to predict the disease severity and clinical progression of COVID-19. 8,9 It has been suggested that COVID-19 enters the body cells through binding to angiotensin-converting enzyme-2 (ACE2) receptor, 10 which mainly helps in blood pressure regulation. This type I membrane protein is expressed in endothelium and body organs including lungs, heart, kidneys, and intestines at varying levels, 11 which renders these tissues more vulnerable to damage by COVID-19. 12,13 It has been shown that serum albumin (SA) levels result in downregulation of ACE2. 14 Additionally, lower SA concentrations were seen in severe forms of COVID-19 in comparison with less severe forms. 15 Other studies have also emphasized the significance of measuring this parameter in patients with COVID-19. 16 Therefore, the study of its predictive value for severity and mortality in COVID-19 is of great importance.
Blood urea nitrogen (BUN), the end product of nitrogen metabolism, has been previously suggested as a useful predictor of cardiovascular morbidity and mortality, 17 as well as mortality in patients with H1N1 pneumonia. 18 In terms of COVID-19, elevated baseline BUN levels were associated with severe COVID-19 and adverse outcomes. 19 On the other hand, the B/A ratio had shown a high predictive value for in-hospital mortality in COVID-19 patients. 20   fatigue, cough (with or without sputum), anorexia, myalgia, sore throat, dyspnea, nasal congestion, headache, and rarely diarrhea and nausea/vomiting. Severe cases were defined as COVID-19 cases with severe pneumonia, presenting with fever or respiratory infection with a respiratory rate ≥30/min or SpO 2 ≤ 93% at room air.
One blood sample was taken from all patients within 4 h of their admission in a standing position, collected in plain tubes, and sent to the laboratory within 2 h after collection. In the lab, the samples were kept at 2-8°C. For testing, the serum/plasma was separated from the samples by centrifuge and evaluated for the levels of BUN, albumin, and other electrolytes. BUN was measured using the enzymatic method with urease and glutamate dehydrogenase and SA level using Bromocresol green method and Latex coagulating nephelometric assay; other biochemical markers were measured using standard methods. The B/A ratio (mg/g) was calculated by dividing the BUN level (mg/l) by the albumin level (g/l).
The clinical progression and outcome of the disease in terms of survival or mortality were assessed 30 days after hospitalization by telephone calls and hospital records. In the case of posthospitalization death, the cause of death was asked from their first-degree relative.
The protocol of the study was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences (code: IR.SBMU.R-ETECH.REC.1399.466). Any patient who was referred to another center or patients who did not respond to the 30-day telephone call were considered lost to follow-up and excluded from the study.

| Statistical analysis
All statistical analyses were performed using the statistical software SPSS (version 25) and R (version 4.1.2). Two-sided p < 0.05 were considered statistically significant. Categorical and continuous variables were presented as frequency, percentage, median, and interquartile range (IQR). The normality distribution of data was checked by the Kolmogorov-Smirnov test. Subsequently, the Mann-Whitney test was performed to compare age, duration of hospitalization, albumin, and B/A ratio between the subgroups of outcome variables. Associations between categorical variables were analyzed by the χ 2 test or Fisher's exact test.
Multiple logistic regression was used to evaluate the association between each dichotomized disease severity and the B/A ratio.
The Hosmer-Lemeshow test was applied to assess the goodness of fit for the logistic regression models. The area under the receiver operating characteristic (ROC) curve was used for the prediction of disease severity and in-hospital mortality by B/A ratio.

| RESULTS
Complete records of 433 COVID-19 patients were available. The  There was no difference in mean SA level among patients with different disease severities, while it was significantly lower in deceased patients compared to alive ones (3.9 vs. 4.3 g/dl, p < 0.0001). The mean B/A ratio was significantly higher in deceased patients, compared to alive ones (8.8 vs. 3.6; p < 0.0001) and also different among patients with different disease severities except for the mild one ( Table 1).
Results of the logistic regression model for B/A ratio on the study outcomes, adjusted for age and sex, revealed B/A ratio as an independent risk factor for sepsis (adjusted odds ratio = 1.060, 95%  Hosmer-Lemeshow tests were performed to approve that the model fits well with the data (p > 0.05). F I G U R E 2 Receiver operator characteristic curves for prediction of disease severities and in-hospital mortality by B/A ratio. B/A, blood urea nitrogen to serum albumin; ROC, receiver operating characteristic low SA levels (<3.5 g/dl) on COVID-19 progression to respiratory failure and its significance as a predictor of COVID-19 outcome, independent of age and comorbidities has been well described. The underlying mechanism of this association has been suggested to be related to the downregulation of ACE2 by SA, as well as the association of hypoalbuminemia with coagulopathy. 14 19 Additionally, another study also showed BUN/creatinine ratio as an independent predictor of COVID-19 severity and survival. 30 The underlying mechanism of this association has been suggested to be related to the expression of ACE2 receptors in kidneys, which results in activating the renin-angiotensin-aldosterone system and increases the absorption of water and sodium in the kidney tubules, causing passive reabsorption of BUN, renal vasoconstriction, and worse prognosis in patients with underlying renal dysfunction. 31 The We hypothesized that the combination of BUN and SA levels (B/A ratio), previously indicated as an important predictor of progression of pneumonia into critical conditions 33  and Behzad Hajimoradi (the corresponding author).

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.